Pneumoviruses, such as human respiratory syncytial virus (hRSV), are viruses that cause respiratory tract infections. Infection with hRSV is widespread. Although infection in adults is usually mild (or even asymptomatic), with any symptoms similar to those of the common cold, the virus can cause severe lower respiratory tract infections in young children or the elderly.
Pneumovirus infections are also commonplace in animals, particularly cows, sheep and goats, with bovine RSV (bRSV), ovine RSV and caprine RSV respectively. An additional pneumovirus, pneumonia virus of mice (PVM), has been shown to infect a wide range of species including rodents, dogs and humans. The pneumoviruses display structural and functional homology, and similar respiratory tract infections in animals.
The current treatment options for hRSV are limited. There is therefore a need for new treatments for hRSV infection and other pneumovirus infections.
DEAD box RNA helicases are a family of ATP-dependent RNA helicase enzymes. These enzymes have a conserved sequence Asp-Glu-Ala-Asp (DEAD). DDX3X is a DEAD box RNA helicase, encoded by the DDX3X gene. DDX3X and homologs thereof can be found in humans and other mammals, such as cows and sheep. DEAD box proteins are associated with many processes ranging from RNA synthesis, RNA degradation and translation initiation. A DDX3X homologue expressed from a gene on the Y chromosome shares 91% sequence identity.
It is known that infection with HIV-1 or HCV (hepatitis C virus) can lead to DDX3X expression being induced, and that certain cancer types are associated with overexpression of DDX3X. Thus, WO 2011/039735 describes the use of certain DDX3X inhibitors to suppress in vitro activity of DDX3X, suppress HIV-1 replication, and suppress proliferation of tumour cell lines. DDX3X does not apparently play a role in regulating HIV-1 transcription, but apparently acts as a nucleo-cytoplasmic shuttling protein for the export of HIV-1 transcripts. Similarly, DDX3X is known to interact with HCV core proteins, and alter their intracellular location. However, no link has previously been suggested between DDX3X and pneumovirus infection.
Pneumovirus replication requires translation of two open reading frames (ORF) from the M2 mRNA. ORF-2 overlaps with ORF-1. Host ribosomes access and translate the pneumovirus M2 ORF-2 by using one of two or three AUG codons located upstream of the ORF-1 termination codon. Expression from these initiation codons requires the prior termination of M2 ORF-1 translation. The hRSV M2-2 protein produced by coupled translation has been proposed to be involved in the switch between virus transcription and replication.